RT Journal Article SR Electronic T1 Activation of rod input in a model of retinal degeneration reverses retinal remodeling and induces formation of normal synapses, circuitry and visual signaling in the adult retina JF bioRxiv FD Cold Spring Harbor Laboratory SP 469221 DO 10.1101/469221 A1 Wang, Tian A1 Pahlberg, Johan A1 Cafaro, Jon A1 Sampath, Alapakkam P. A1 Field, Greg D. A1 Chen, Jeannie YR 2018 UL http://biorxiv.org/content/early/2018/11/13/469221.abstract AB A major cause of human blindness is the death of rod photoreceptors. As rods degenerate, synaptic structures between rod and rod bipolar cells dissolve and the rod bipolar cells extend their dendrites and occasionally make aberrant contacts. Such changes are broadly observed in blinding disorders caused by photoreceptor cell death and is thought to occur in response to deafferentation. How the remodeled retinal circuit affect visual processing following rod rescue is not known. To address this question, we generated transgenic mice wherein a disrupted cGMP-gated channel (CNG) gene can be repaired at the endogenous locus and at different stages of degeneration by tamoxifen-inducible cre-mediated recombination. In normal rods, light-induced closure of CNG channels leads to hyperpolarization of the cell, reducing neurotransmitter release at the synapse. Similarly, rods lacking CNG channel exhibit a resting membrane potential that was ~10mV hyperpolarized compared to WT rods, indicating diminished glutamate release. Retinas from these mice undergo stereotypic retinal remodeling as a consequence of rod malfunction and degeneration. Upon tamoxifen-induced expression of CNG channels, rods recovered their structure and exhibited normal light responses. Moreover, we show that the adult mouse retina displays a surprising degree of plasticity upon activation of rod input. Wayward bipolar cell dendrites establish contact with rods to support normal synaptic transmission, which is propagated to the retinal ganglion cells. These findings demonstrate remarkable plasticity extending beyond the developmental period and support efforts to repair or replace defective rods in patients blinded by rod degeneration.Significance Statement Current strategies for treatment of neurodegenerative disorders are focused on the repair of the primary affected cell type. However, the defective neuron functions within a complex neural circuitry, which also becomes degraded during disease. It is not known whether a rescued neuron and the remodeled circuit will establish communication to regain normal function. We show that the adult mammalian neural retina exhibits a surprising degree of plasticity following rescue of rod photoreceptors. The wayward rod bipolar cell dendrites re-establish contact with rods to support normal synaptic transmission, which is propagated to the retinal ganglion cells. These findings support efforts to repair or replace defective rods in patients blinded by rod cell loss.This work was supported by National Institute of Health grants EY027193 (APS, GDF, and JC); EY12155 and EY027387 (JC); an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology, UCLA; and Jules Stein Eye Institute Core Grant EY00331 (APS). We thank Dr. M. Scalabrino for comments on the manuscript, Dr. K.Martemyanov for providing the mGluR6 antibody, Dr. C. Craft for providing the cone arrestin (ARR3) antibody and Dr. S. Ruffins at the USC microscopy core for his help with confocal imaging.